WO1996024362A1 - Antiinflammatory agents - Google Patents

Antiinflammatory agents Download PDF

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Publication number
WO1996024362A1
WO1996024362A1 PCT/JP1996/000239 JP9600239W WO9624362A1 WO 1996024362 A1 WO1996024362 A1 WO 1996024362A1 JP 9600239 W JP9600239 W JP 9600239W WO 9624362 A1 WO9624362 A1 WO 9624362A1
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Prior art keywords
sulfated
group
polysaccharide
disease
hyaluronic acid
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PCT/JP1996/000239
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French (fr)
Japanese (ja)
Inventor
Kazuo Akima
Peter A. Ward
Masayuki Miyasaka
Yasuo Suzuki
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Shiseido Company, Ltd.
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Application filed by Shiseido Company, Ltd. filed Critical Shiseido Company, Ltd.
Priority to US08/722,131 priority Critical patent/US5872109A/en
Priority to DE69621528T priority patent/DE69621528T2/en
Priority to EP96901544A priority patent/EP0754460B1/en
Publication of WO1996024362A1 publication Critical patent/WO1996024362A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate

Definitions

  • the present invention relates to an anti-inflammatory agent and the like having a novel mechanism of action. More specifically, the present invention relates to the use of sulfated acidic mucopolysaccharide or sulfated dextran screened based on a novel mechanism of action for the treatment or prevention of inflammation and the like.
  • corticoids or various non-steroid anti-inflammatory drugs are widely used clinically to suppress or block the inflammatory response and prevent complications due to inflammation.
  • corticoid has a strong anti-inflammatory effect, but cannot be administered continuously due to serious side effects such as induction of infections, and non-steroidal anti-inflammatory drugs are generally ineffective. Therefore, it is still necessary to develop an anti-inflammatory drug that shows little side effects and has sufficient efficacy.
  • disk renin grayed system that led to anti-inflammatory agents as described above is developed, generally, anti-prostaglandin action (e.g., Fosufuora Ipesu A 2 inhibitors, cyclo-O alkoxy diethyl Natick be inhibited, Ripokishijiwene scan inhibition ) Is used as an index.
  • anti-prostaglandin action e.g., Fosufuora Ipesu A 2 inhibitors, cyclo-O alkoxy diethyl Natick be inhibited, Ripokishijiwene scan inhibition
  • the present invention provides a screening system (ie, inhibition of neutrophil infiltration, more specifically, vascular endothelial cells) based on the knowledge of inflammation induction that has recently become apparent.
  • a screening system based on selectin-mediated inhibition of cell adhesion as a marker, there is a possibility that a completely new type of anti-inflammatory agent can be developed. Things.
  • adhesion molecules are present on leukocytes and activated vascular endothelial cells (blood vessels at the site of inflammation), and that the interaction of these adhesion molecules is the first essential step for leukocyte infiltration into inflamed areas. .
  • these adhesion molecules are expressed in both leukocytes and vascular endothelial cells, and selectin family and integrin family are the most important.
  • substances screened using the above-described experimental animal model suppress selectin-mediated neutrophil infiltration of vascular endothelial adhesive tissues, and are therefore effective not only in ARDS but also in general in inflammation. It was also found to be effective against ischemic heart disease, ischemic brain disease, rheumatoid arthritis, atopic dermatitis, and invasion after organ transplantation.
  • a polysaccharide selected from the group consisting of sulfated acidic mucopolysaccharide, sulfated dextran and a physiologically acceptable salt thereof, and a pharmaceutical auxiliary.
  • Anti-inflammatory agents are provided.
  • a method for treating inflammation using the polysaccharide A law is provided. More specifically, according to the present invention, adult respiratory distress syndrome (ARDS) using a polysaccharide selected from the group consisting of sulfated acidic mucopolysaccharide, sulfated dextran and a physiologically acceptable salt thereof
  • ARDS adult respiratory distress syndrome
  • a method for treating a disease selected from the group consisting of ischemic heart disease, ischemic brain disease, rheumatoid arthritis, atopic dermatitis and infiltration after organ transplantation is provided.
  • a polysaccharide selected from the group consisting of sulfated acidic mucopolysaccharide, sulfated dextran and a physiologically acceptable salt thereof for producing a medicament for treating a disease.
  • the sulfated acidic mucopolysaccharides used in the present invention include hexosamine (often N-acetylated dalcosamine or galactosamine) and peronic acid (D-glucuronic acid or L-iduronic acid). ) Is a long-chain polysaccharide having a repeating unit of disaccharide, and having a sulfate group. Since some acidic mucopolysaccharides of natural origin have a sulfate group, those themselves and, if necessary, those chemically chemically sulfated are also included in the sulfated acidic mucopolysaccharide according to the present invention.
  • acidic mucopolysaccharides having no sulfate group can be used in the present invention by chemically introducing a sulfate group.
  • acidic mucopolysaccharides include those having a sulfate group such as chondroitin 4-sulfate and 6-sulfate, dermatan sulfate, heparan sulfate (also called heparitin sulfate), heparin sulfate.
  • Keratan sulphate is mentioned, and those without sulphate groups include hyaluronic acid and chondroitin.
  • sulfated dextran can also be used. These include partial sulfates which are known to have a heparin-like anticoagulant effect and are also used clinically.
  • sulfated hyaluronic acid is particularly preferred from the viewpoints of availability of raw materials and efficacy.
  • Such sulfated hyaluronic acid is derived from a wide range of natural sources, such as mammalian connective tissue, chicken crest, silkworm gastric membrane, and streptococcal capsular hyaluronic acid (? -D-). It is a compound obtained by sulfated N-acetylglucosamine and / 3-D-glucanoic acid (alternately linked linear polysaccharide).
  • hyaluronic acid has molecular weight dispersibility depending on the type of source, no structural heterogeneity is known, so that any source can be used.
  • those derived from streptococci can be conveniently used.
  • Specific examples thereof include hyaluronic acid prepared according to the method described in JP-A-58-26692. It generally has a molecular weight of about 2.000 kDa.
  • the molecular weight of hyaluronic acid is adjusted as necessary by partial hydrolysis, etc., and if short-term efficacy of the final product is expected, a low-molecular-weight product (hereinafter abbreviated as LMWHA) will be used.
  • LMWHA low-molecular-weight product
  • Sulfation of hyaluronic acid can be carried out in a manner known per se, and it is preferable to use a sulfate / trimethylamine complex as a sulfating agent.
  • the ratio of the use of hyaluronic acid and the sulfating agent can be arbitrarily selected according to the desired sulfation rate (or sulfur content) of the sulfated hyaluronic acid and the reaction conditions.
  • the amount of the sulfating agent is selected so as to be about 2 fg of the weight of hyaluronic acid.
  • the sulphation rate achieved in this way is generally about 50 to 60% per total hydroxyl groups of hyaluronic acid.
  • the resulting sulfated hyaluronic acid can be purified by a purification operation commonly used for various modified polysaccharides.
  • Specific purification operations include a step of concentrating the reaction mixture under reduced pressure, dialyzing against distilled water, desalting, removing trimethylamine by trifluoroacetic acid treatment, and then freeze-drying.
  • acidic mucopolysaccharides can also be converted to the corresponding sulfated acidic mucopolysaccharides according to the sulfation treatment of hyaluronic acid.
  • Optimum values for the molecular weight and the degree of sulfation vary depending on the type of saccharide, and those skilled in the art will be able to easily select these optimum values through a pharmacological test or the like described later.
  • Sulfated acidic mucopolysaccharide or sulfated dextran is used as a physiologically acceptable salt form, if necessary, by subjecting it to a hydroxide or carbonate of alkali metal or a salt-forming reaction using an amine. You can also.
  • sulfated acidic mucopolysaccharide or sulfated dextran or a physiologically acceptable salt thereof is used in combination with pharmaceutical auxiliaries such as diluents or excipients used in the preparation of ordinary pharmaceutical preparations. It can be mixed and administered parenterally into solutions and suspensions, intravenously, intraarterially or intraperitoneally.
  • Pharmaceutical auxiliaries commonly used in solutions include, for example, water, ethyl alcohol and Pyrene glycol; and for suspending agents, polyoxyethylene sorbitol and sorbitan esters.
  • the mixing ratio of the adjuvant and the sulfated acidic polysaccharide or sulfated dextran is not limited because the optimum ratio varies depending on the dosage form.However, when preparing sulfated hyaluronic acid for injection, use physiological saline. Sulfated hyaluronic acid in water 0.01 to: I 0 (weight Z volume)%, preferably 0.05 to 1 (weight volume)%, is convenient for treatment of patients. Needless to say, the above-mentioned injection solution may be prepared just before use as a concentrated preparation.
  • sulfated hyaluronic acid as an active ingredient varies depending on the age of the patient, the type and extent of the disease, and the dosage form and administration mode, but in the case of intravenous injection, it is 0.01. It can be administered in a dose of 0.1 to 10 mg OgZkg. Sulfated hyaluronic acid and other sulfated acidic mucopolysaccharides and sulfated dextran do not show acute toxicity even at a dose of 200 rag Zkg or more. May be used.
  • the anti-inflammatory agent of the present invention as described above is widely used because it significantly suppresses vascular permeability, bleeding associated with inflammation, and myeloperoxidase (MPO) activity in an experimental animal model induced by administration of cobra venom. It can be used as an anti-inflammatory agent, especially for the prevention or treatment of ARDS, ischemic heart disease, ischemic brain disease, rheumatoid arthritis, atopic dermatitis, and invasion after organ transplantation.
  • MPO myeloperoxidase
  • Production Example 1 Dissolve 20 Omg of high molecular weight hyaluronic acid (HMWHA, molecular weight 1.300 kDa) and 400 mg of 'trinotylamine sulfate complex (Aldrich) in 6 mL of dimethylformamide, and in an oil bath at 50-60 ° C. Stirred for one week. After the reaction solution was concentrated under reduced pressure using a vacuum pump, the residue was dissolved in water, dialyzed against deionized water overnight, and then freeze-dried. The obtained dried product was dissolved in 2 mL of water, and trifluoroacetic acid (equivalent to 1.5 times the total number of hydroxyl groups of HMWHA) was added, followed by stirring at room temperature for 1 hour. After dialysis, the reaction solution was freeze-dried to obtain 20 mg of sulfated hyaluronic acid having a sulfation rate of about 60%.
  • HMWHA high molecular weight hyaluronic acid
  • Aldrich
  • Cobra venom was isolated from crude cobra (Naja naja) venom by the method described by Till et al., J. Clin. Invest., 69, 1126-1135, 1982. 20 U / kg body weight of CVF was injected intravenously into a fixed volume of 125 I-BSA (0.5 Ci) and 51 Cr-rat erythrocytes (RBC).
  • ketamine hydrochloride (10 OmgZkg) (Parke Davis and Co.) and blood was collected from the dorsal vena cava 30 minutes after CVF injection.
  • Negative control animals were treated as above, except that phosphate buffered saline (PBS, pH 7.4) was used instead of CVF.
  • PBS phosphate buffered saline
  • the lung vasculature Perfused through the right ventricle with 1 OmL of PBS.
  • the lungs were removed, and the vascular system was perfused with 1 OmL of sterile physiological saline, and then the amount of radioactivity remaining in the tissues was measured with a gamma scintillation counter.
  • the positive control is the value measured when the test substance was not administered.
  • Pulmonary damage is measured by increasing pulmonary vascular permeability (by determining the ratio of the amount of 125 I-BSA radioactivity present in lung tissue to the amount of radioactivity present in the venous blood lniL obtained at death) as well as blood. Hemorrhage was determined by bleeding (based on 51 Cr-RBC radioactivity) as a percentage of radioactivity. The protection against lung injury was calculated by the following formula.
  • the MP0 activity of the tissue was measured. After a certain number of intraperitoneal neutrophils of glycogen-stimulated rats were added to the lungs of normal rats, the tissues were homogenized and extracted, and a standard curve was prepared (Warren et al., J. Clin. Invest., 84, 1873-1882, 1989).
  • the lung sample was homogenized with a homogenizer (Polytron: Tekmar Co.,) set to 4 using 6 mL of a solution (5 OmM phosphate, pH 6.0), homogenized for 4 x 10 seconds, and then centrifuged at 4 ° C. (3,000g, 30 minutes).
  • the MPO activity in the supernatant, 0 - H 2 0 absorbance resulting from the second consumer in the presence of Jianishijin changes in (46 onm) was assessed by measuring.
  • the sulfated polysaccharide of the present invention can significantly protect lung damage caused by administration of cobra venom (CVF).
  • CVF cobra venom
  • anti-inflammatory agents having a different mechanism of action from conventional anti-inflammatory agents
  • the anti-inflammatory agent of the present invention uses a sulfated acidic mucopolysaccharide or a sulfated dextran as an active ingredient, thereby exhibiting a strong anti-inflammatory action and the like, and inflammation, particularly ARDS, ischemic heart disease, ischemic Methods are provided for treating or preventing brain disease, rheumatoid arthritis, atopic dermatitis and infiltration after organ transplantation.
  • the present invention has utility in the pharmaceutical industry.

Abstract

Applications of polysaccharides selected from the group consisting of sulfated acid mucopolysaccharides, sulfated dextrans and physiologically acceptable salts thereof to the prevention or treatment of various inflammatory diseases such as adult respiratory distress syndrome (ARDS), ischemic heart diseases, ischemic brain diseases, rheumatoid arthritis, atopic dermatitis, and infiltration after organ transplantation.

Description

明細書  Specification
抗炎症剤  Anti-inflammatory agent
技術分野  Technical field
本発明は新規な作用機序を有する抗炎症剤等に関する。 より具体的に は、 新規な作用機序に基づいてスクリーニングされた硫酸化酸性ムコ多 糖類または硫酸化デキス 卜ランの炎症等の治療または予防への使用に関 する。  The present invention relates to an anti-inflammatory agent and the like having a novel mechanism of action. More specifically, the present invention relates to the use of sulfated acidic mucopolysaccharide or sulfated dextran screened based on a novel mechanism of action for the treatment or prevention of inflammation and the like.
発明の背景  Background of the Invention
現在、 炎症反応を抑制または遮断し、 炎症による合併症を防ぐ目的で コルチコィ ドまたは各種の非ステロイ ド系抗炎症剤が臨床上広く使用さ れている。 しかし、 コルチコィ ドは強い抗炎症作用を示すものの感染症 の誘発等の重篤な副作用を伴うので連続投与ができず、 また非ステロイ ド系抗炎症剤は一般的に効力が弱い。 そのため、 副作用を殆ど示さず、 十分な効能を有する抗炎症剤の開発が必要であることに変わりはない。 ところで、 上記のような抗炎症剤が開発されるに至ったスク リーニン グ系は、 一般的に、 抗プロスタグランジン作用 （例えば、 フォスフオラ ィペース A 2阻害、 サイクロォキシジエネース阻害、 リポキシジヱネー ス阻害） を指標としたものである。 これに対し、 本発明では、 近年明ら かになりつつある炎症の誘発に関する知見を基に構成したスクリーニン グ系 （すなわち、 好中球の浸潤阻害、 より具体的には、 血管内皮細胞へ の接着のセレクチン介在性阻害を指標にしたスクリ一二ング系） を利用 すれば、 まったく新たなタイプの抗炎症剤を開発できる可能性があると の観点に立ち、 前記課題を解決しょうとするものである。 Currently, corticoids or various non-steroid anti-inflammatory drugs are widely used clinically to suppress or block the inflammatory response and prevent complications due to inflammation. However, corticoid has a strong anti-inflammatory effect, but cannot be administered continuously due to serious side effects such as induction of infections, and non-steroidal anti-inflammatory drugs are generally ineffective. Therefore, it is still necessary to develop an anti-inflammatory drug that shows little side effects and has sufficient efficacy. Meanwhile, disk renin grayed system that led to anti-inflammatory agents as described above is developed, generally, anti-prostaglandin action (e.g., Fosufuora Ipesu A 2 inhibitors, cyclo-O alkoxy diethyl Natick be inhibited, Ripokishijiwene scan inhibition ) Is used as an index. In contrast, the present invention provides a screening system (ie, inhibition of neutrophil infiltration, more specifically, vascular endothelial cells) based on the knowledge of inflammation induction that has recently become apparent. Using a screening system based on selectin-mediated inhibition of cell adhesion as a marker, there is a possibility that a completely new type of anti-inflammatory agent can be developed. Things.
ここで、 本発明で用いるスクリ一二ング系の意義を明らかにする目的 でその背景となる知見を概観しておく。 例えば、 炎症の誘発は白血球と 血管内皮細胞間の接着相互作用を促進する分子に起因するものと考えら れており、 一定の接着分子が上記接着作用を促進する上で重要な役割を 演じていることも明らかになつてきた。 また、 白血球と活性化血管内皮 細胞 （炎症部位の血管） に接着分子が存在し、 それらの接着分子の相互 作用が炎症局所への白血球の浸潤に関する最初の必須段階であることも 判明している。 なお、 これらの接着分子は白血球および血管内皮細胞の 双方で発現される分子であり、 セレクチンフアミ リーおよびインテグリ ンフアミ リ一が最も重要である。 Here, the purpose of clarifying the significance of the screening system used in the present invention An overview of the background is given below. For example, the induction of inflammation is thought to be due to molecules that promote the adhesive interaction between leukocytes and vascular endothelial cells, and certain adhesion molecules play an important role in promoting the above-mentioned adhesive action. It has become clear that it is. It has also been shown that adhesion molecules are present on leukocytes and activated vascular endothelial cells (blood vessels at the site of inflammation), and that the interaction of these adhesion molecules is the first essential step for leukocyte infiltration into inflamed areas. . In addition, these adhesion molecules are expressed in both leukocytes and vascular endothelial cells, and selectin family and integrin family are the most important.
他方、 上記相互作用を制御する目的で、 モノ クローナル抗体 (Eur. J . I mmunol. 2_3. 2181— 2188, 1993) 、 ぺプチド類を 始め、 その他一定のオリゴ糖の使用も報告されている （ J . Cell Bi ol.. 9_9, 1535, 1984 ； J . Cell Biol. , 104, 713, 1987 : Blood., 70, 1842, 1987) 。 さらに、 上記セレ クチンの作用を介してリ ンパ節内の内皮細胞に白血球が接着するがこの 反応は一定の硫酸基含有化合物によって阻害されることが明らかにされ ている （ J . Cell Biol., I l l, 1225, 1 990) 。 またさ らに、 各種実験動物モデルにおいて、 前記接着相互作用を阻害すること により炎症反応を抑制できることも報告されている （ J . I mmunol., 150, 2407, ： J . I mmunol. 150. 1074. 他） 。  On the other hand, for the purpose of controlling the above-mentioned interaction, the use of monoclonal antibodies (Eur. J. Immunol. 2_3. 2181—2188, 1993), peptides, and certain other oligosaccharides has also been reported ( J. Cell Biol .. 9_9, 1535, 1984; J. Cell Biol., 104, 713, 1987: Blood., 70, 1842, 1987). Furthermore, it has been shown that leukocytes adhere to endothelial cells in lymph nodes through the action of the above-mentioned selectins, but this reaction is inhibited by certain sulfate-containing compounds (J. Cell Biol., Ill, 1225, 1 990). In addition, it has been reported in various experimental animal models that the inflammatory reaction can be suppressed by inhibiting the adhesion interaction (J. Immunol., 150, 2407, J. Immunol. 150. 1074). . other) .
しかし、 上記のようなモノクローナル抗体、 ペプチド類、 オリゴ糖お よび硫酸基含有化合物が現実に抗炎症剤として使用できるか否かについ ては明らかにされていない。  However, it has not been clarified whether the monoclonal antibodies, peptides, oligosaccharides, and sulfate group-containing compounds as described above can actually be used as anti-inflammatory agents.
本発明者らは、 最近、 M. S. Mulliganら、 Nature, 364, 1 9一 15 1， 1993により提案されたコブラ毒 （Cobra venon fac tor, 以下 「CVF」 と略記する場台もある） のラ ッ 卜静脈内投与によ る好中球依存性および酸素ラジカル介在性で、 かつ P—、 L一または E —セレクチン依存性の炎症モデルが、 抗炎症剤の優れたスクリ一二ング 手段であることを見い出した。 より具体的には、 上記実験動物モデルを 使用してスクリ一ニングした硫酸化ヒアル口ン酸等の特定の多糖類が優 れた抗炎症作用を示し、 殊に成人性呼吸切迫症候群 （adult respirato ry distress syndrome : A R D S ) の予防または治療に使用できるこ とを見い出した。 前記症候群は発病者の 50〜70%が死亡する重篤な 疾病である （医学のあゆみ、 168 (n o. 6) , 626— 631 ) 。 また、 上記実験動物モデルを用いてスク リーニングされる物質は、 セレ クチンが介在する好中球の血管内皮接着組織浸潤を抑制するので、 AR DSのみならず広く炎症一般に効能を示し、 さらには虚血性心疾患、 虚 血性脳疾患、 慢性関節リューマチ、 ア トピー性皮膚炎、 臓器移植後の浸 潤に対しても効能を示すことも見い出した。 The present inventors have recently described MS Mulligan et al., Nature, 364, 1 Neutrophil dependence and oxygen radical mediated by intravenous injection of cobra venom (CVF), proposed by 1991 And P-, L- or E-selectin-dependent inflammation models have been found to be excellent screening tools for anti-inflammatory agents. More specifically, specific polysaccharides such as sulfated hyaluronic acid screened using the above-described experimental animal model show excellent anti-inflammatory effects, and in particular, adult respiratory distress syndrome (adult respirato ry distress syndrome (ARDS). The syndrome is a serious illness that kills 50-70% of affected individuals (Advance in Medicine, 168 (no. 6), 626-631). In addition, substances screened using the above-described experimental animal model suppress selectin-mediated neutrophil infiltration of vascular endothelial adhesive tissues, and are therefore effective not only in ARDS but also in general in inflammation. It was also found to be effective against ischemic heart disease, ischemic brain disease, rheumatoid arthritis, atopic dermatitis, and invasion after organ transplantation.
なお、 硫酸化ヒアルロン酸を始めようとする各種糖類の硫酸化物はヒ ト免疫不全ウイルス性疾患の処置に使用しうることが示唆されている （特 公平 2— 7577号公報） が、 それらの糖類が抗炎症剤として使用でき ることについては従来技術文献に未載である。  It has been suggested that sulfates of various sugars such as sulfated hyaluronic acid can be used for the treatment of human immunodeficiency virus disease (Japanese Patent Publication No. 2-7577). There is no publication in the prior art literature regarding that can be used as an anti-inflammatory agent.
発明の開示 Disclosure of the invention
従って、 本発明によれば、 硫酸化酸性ムコ多糖類、 硫酸化デキス トラン およびそれらの生理学的に許容される塩からなる群より選ばれる多糖類 の有効量と製薬学的助剤とを含んでなる抗炎症剤が提供される。 Therefore, according to the present invention, it comprises an effective amount of a polysaccharide selected from the group consisting of sulfated acidic mucopolysaccharide, sulfated dextran and a physiologically acceptable salt thereof, and a pharmaceutical auxiliary. Anti-inflammatory agents are provided.
また、 別の態様の本発明に従えば、 前記多糖類を用いる炎症の治療方 法が提供される。 より具体的には、 本発明に従えば、 硫酸化酸性ムコ多 糖類、 硫酸化デキストランおよびそれらの生理学的に許容される塩から なる群より選ばれる多糖類を用いる成人性呼吸切迫症候群 （A R D S ) . 虚血性心疾患、 虚血性脳疾患、 慢性関節リユーマチ、 ァ トピー性皮膚炎 および臓器移植後の浸潤からなる群より選ばれる疾患の治療方法が提供 される。 According to another aspect of the present invention, there is provided a method for treating inflammation using the polysaccharide. A law is provided. More specifically, according to the present invention, adult respiratory distress syndrome (ARDS) using a polysaccharide selected from the group consisting of sulfated acidic mucopolysaccharide, sulfated dextran and a physiologically acceptable salt thereof A method for treating a disease selected from the group consisting of ischemic heart disease, ischemic brain disease, rheumatoid arthritis, atopic dermatitis and infiltration after organ transplantation is provided.
また、 さらに別の態様の本発明に従えば、 炎症、 ならびに A R D S、 虚血性心疾患、 虚血性脳疾患、 慢性関節リューマチ、 ア ト ピー性皮膚炎 および臓器移植後の浸潤からなる群より選ばれる疾患の治療用薬剤を製 造するための硫酸化酸性ムコ多糖類、 硫酸化デキス トランおよびそれら の生理学的に許容される塩からなる群より選ばれる多糖類の使用が提供 される。  According to still another aspect of the present invention, it is selected from the group consisting of inflammation, and ARDS, ischemic heart disease, ischemic brain disease, rheumatoid arthritis, atopic dermatitis and infiltration after organ transplantation. There is provided use of a polysaccharide selected from the group consisting of sulfated acidic mucopolysaccharide, sulfated dextran and a physiologically acceptable salt thereof for producing a medicament for treating a disease.
発明の詳細な記述 Detailed description of the invention
本発明で使用する硫酸化酸性ムコ多糖類とは、 へキソサミ ン （多くの 場合 N -ァセチル化されたダルコサミ ンまたはガラク 卜サミ ン） とゥロ ン酸 （D -グルクロン酸または L -ィズロン酸） よりなる二糖の繰り返し 単位をもつ長鎖多糖類であって、 硫酸基を有するものを意味する。 天然 由来の酸性ムコ多糖類には硫酸基をもつものもあるので、 それら自体お よび必要により、 さらに化学的に硫酸化したものも本発明にいう硫酸化 酸性ムコ多糖類に包含される。 また、 硫酸基をもたない酸性ムコ多糖類 は、 化学的に硫酸基を導入することによって本発明で使用可能になる。 かかる酸性ムコ多糖類の具体例としては、 硫酸基をもつものとして、 コン ドロイチン 4 -硫酸および 6 -硫酸、 デルマタン硫酸、 へパラン硫酸 (またはへパリチン硫酸とも称されている） 、 へパリ ン硫酸、 ならびに ケラタン硫酸が挙げられ、 硫酸基をもたないものとして、 ヒアルロン酸 ならびにコンドロイチンが挙げられる。 The sulfated acidic mucopolysaccharides used in the present invention include hexosamine (often N-acetylated dalcosamine or galactosamine) and peronic acid (D-glucuronic acid or L-iduronic acid). ) Is a long-chain polysaccharide having a repeating unit of disaccharide, and having a sulfate group. Since some acidic mucopolysaccharides of natural origin have a sulfate group, those themselves and, if necessary, those chemically chemically sulfated are also included in the sulfated acidic mucopolysaccharide according to the present invention. Further, acidic mucopolysaccharides having no sulfate group can be used in the present invention by chemically introducing a sulfate group. Specific examples of such acidic mucopolysaccharides include those having a sulfate group such as chondroitin 4-sulfate and 6-sulfate, dermatan sulfate, heparan sulfate (also called heparitin sulfate), heparin sulfate. , And Keratan sulphate is mentioned, and those without sulphate groups include hyaluronic acid and chondroitin.
本発明では、 さらに、 硫酸化デキストランも使用できる。 これらには、 へパリン様の抗血液凝固作用を有することが知られていて、 臨床的にも 使用されてている部分的硫酸エステルも包含される。  In the present invention, sulfated dextran can also be used. These include partial sulfates which are known to have a heparin-like anticoagulant effect and are also used clinically.
以上の各種硫酸化糖類のうち、 特に硫酸化ヒアルロン酸が、 原料の入 手容易性および効能の観点から好ましい。 かかる硫酸化ヒアル口ン酸は、 広範な天然起源、 例えば哺乳動物の結合組織、 ニヮ トリのとさか、 カイ コの胃腔膜、 連鎖球菌の莢膜などに由来するヒアルロン酸 （ ?-D- N- ァセチルグルコサミ ンと /3-D-グルク口ン酸が交互に結合してできた直 鎖状の高分子多糖） を硫酸化することにより得られる化合物である。 一 般に、 ヒアルロン酸は起源の種類によって分子量の分散性が存在するも のの構造上の不均一性は知られていないので、 いずれの起源のものも使 用できる。 しかし、 入手の容易性を考慮すると、 限定されるものでない が、 連鎖球菌に由来するものを都合よく使用することができる。 その具 体的なものとしては、 特開昭 58 - 26692号公報に記載されるよう な方法に從つて調製したヒアルロン酸が挙げられる。 このものは、 一般 に、 分子量約 2. O O O kD aをもつ。 ヒアルロン酸は必要により部分 加水分解等により分子量を調整し、 最終製品の速効性を期待する場合に は、 低分子のもの （以下、 LMWHAと略記する） を、 持铳性を期待す る場合には高分子のもの （以下、 HMWHAと略記する） を使用して硫 酸化処理に付する。  Among the above-mentioned various sulfated saccharides, sulfated hyaluronic acid is particularly preferred from the viewpoints of availability of raw materials and efficacy. Such sulfated hyaluronic acid is derived from a wide range of natural sources, such as mammalian connective tissue, chicken crest, silkworm gastric membrane, and streptococcal capsular hyaluronic acid (? -D-). It is a compound obtained by sulfated N-acetylglucosamine and / 3-D-glucanoic acid (alternately linked linear polysaccharide). In general, although hyaluronic acid has molecular weight dispersibility depending on the type of source, no structural heterogeneity is known, so that any source can be used. However, in view of availability, although not limited, those derived from streptococci can be conveniently used. Specific examples thereof include hyaluronic acid prepared according to the method described in JP-A-58-26692. It generally has a molecular weight of about 2.000 kDa. The molecular weight of hyaluronic acid is adjusted as necessary by partial hydrolysis, etc., and if short-term efficacy of the final product is expected, a low-molecular-weight product (hereinafter abbreviated as LMWHA) will be used. Is subjected to a sulfuric acid treatment using a polymer (hereinafter abbreviated as HMWHA).
ヒアルロン酸の硫酸化は、 それ自体既知の方法で行うことができる力、'、 硫酸化剤として硫酸 · トリメチルァミ ン複合体を使用するものが好まし い。 ヒアルロン酸と硫酸化剤の使用割合は、 目的とする硫酸化ヒアル口 ン酸の硫酸化率 （または硫黄含有率） および反応条件に従って任意に選 ぶことができる。 一般に、 温度 5 0 ~ 6 0 °Cで数 1 0時間から数日間に わたって反応させる場台には、 ヒアルロン酸重量の約 2 fg重量となるよ うに硫酸化剤の量を選ぶ。 こう して達成される硫酸化率は、 ヒアルロン 酸の総水酸基当り約 5 0〜6 0 %のものが一般的である。 Sulfation of hyaluronic acid can be carried out in a manner known per se, and it is preferable to use a sulfate / trimethylamine complex as a sulfating agent. No. The ratio of the use of hyaluronic acid and the sulfating agent can be arbitrarily selected according to the desired sulfation rate (or sulfur content) of the sulfated hyaluronic acid and the reaction conditions. Generally, for a stage where the reaction is carried out at a temperature of 50 to 60 ° C for several 10 hours to several days, the amount of the sulfating agent is selected so as to be about 2 fg of the weight of hyaluronic acid. The sulphation rate achieved in this way is generally about 50 to 60% per total hydroxyl groups of hyaluronic acid.
得られる硫酸化ヒアル口ン酸は、 各種修飾多糖類で常用されている精 製操作によって精製することができる。 具体的な精製操作には、 反応混 台物を減圧濃縮後、 蒸留水に対して透析して脱塩し、 ト リフルォロ酢酸 処理により ト リメチルァミ ンを除去し、 次いで凍結乾燥する工程が含ま れる。  The resulting sulfated hyaluronic acid can be purified by a purification operation commonly used for various modified polysaccharides. Specific purification operations include a step of concentrating the reaction mixture under reduced pressure, dialyzing against distilled water, desalting, removing trimethylamine by trifluoroacetic acid treatment, and then freeze-drying.
他の酸性ムコ多糖類も、 上記ヒアルロン酸の硫酸化処理に準じて、 対 応する硫酸化酸性ムコ多糖類へ転化できる。 分子量および硫酸化率は、 糖の種類により最適値が変動するが、 当業者であればこれらの最適値は、 後述の薬効試験等を通じて容易に選ぶことができるであろう。  Other acidic mucopolysaccharides can also be converted to the corresponding sulfated acidic mucopolysaccharides according to the sulfation treatment of hyaluronic acid. Optimum values for the molecular weight and the degree of sulfation vary depending on the type of saccharide, and those skilled in the art will be able to easily select these optimum values through a pharmacological test or the like described later.
硫酸化酸性ムコ多糖類または硫酸化デキス トランは、 必要により、 ァ ルカリ金属の水酸化物もしくは炭酸塩、 またはァミ ン類などを用いる造 塩反応にかけた生理学的に許容される塩形態として使用することもでき る。  Sulfated acidic mucopolysaccharide or sulfated dextran is used as a physiologically acceptable salt form, if necessary, by subjecting it to a hydroxide or carbonate of alkali metal or a salt-forming reaction using an amine. You can also.
上記の硫酸化酸性ムコ多糖類もしくは硫酸化デキス トランまたはその 生理学的に許容される塩は、 製薬学的な助剤、 例えば、 通常の医薬製剤 の調製に使用される希釈剤または陚形剤と混合し、 液剤および懸濁剤、 静脈内、 動脈内または腹腔内へ非経口的に投与できる。 液剤で通常使用 する製薬学的助剤としては、 例えば、 水、 エチルアルコールおよびプロ ピレングリコールなどが挙げられ、 懸濁剤用としては、 ポリオキシェチ レンソルビトールおよびソルビタンエステル類が挙げられる。 The above-mentioned sulfated acidic mucopolysaccharide or sulfated dextran or a physiologically acceptable salt thereof is used in combination with pharmaceutical auxiliaries such as diluents or excipients used in the preparation of ordinary pharmaceutical preparations. It can be mixed and administered parenterally into solutions and suspensions, intravenously, intraarterially or intraperitoneally. Pharmaceutical auxiliaries commonly used in solutions include, for example, water, ethyl alcohol and Pyrene glycol; and for suspending agents, polyoxyethylene sorbitol and sorbitan esters.
助剤と硫酸化酸性多糖類もしくは硫酸化デキス トランの混合割合は、 剤型によって最適割台が変動するので限定されないが、 硫酸化ヒアルロ ン酸を注射剤として調製する場合には、 生理的食塩水中硫酸化ヒアル口 ン酸 0 . 0 1〜： I 0 (重量 Z容量） ％、 好ましくは 0 . 0 5〜 1 (重量 容量） ％に調製するのが患者の処置上都合がよい。 もちろん、 濃厚製 剤として使用直前に上記のような注射液に調製してもよい。  The mixing ratio of the adjuvant and the sulfated acidic polysaccharide or sulfated dextran is not limited because the optimum ratio varies depending on the dosage form.However, when preparing sulfated hyaluronic acid for injection, use physiological saline. Sulfated hyaluronic acid in water 0.01 to: I 0 (weight Z volume)%, preferably 0.05 to 1 (weight volume)%, is convenient for treatment of patients. Needless to say, the above-mentioned injection solution may be prepared just before use as a concentrated preparation.
有効成分としての硫酸化ヒアルロン酸の投与量は、 患者の年齢、 疾病 の種類および程度、 ならびに剤型および投与様式により最適量は変動す もが、 静脈内注射剤の場合には 0 . 0 1〜 1 0 0 O mgZkg 好ましくは 0 . 1〜 1 O ragZkgで投与できる。 なお、 硫酸化ヒアルロン酸を始めそ の他の硫酸化酸性ムコ多糖類および硫酸化デキス 卜ランは、 2 0 0 O rag Zkg以上の投与量においても急性毒性を示さないので、 上記用量を超え て使用してもよい。  The optimal dose of sulfated hyaluronic acid as an active ingredient varies depending on the age of the patient, the type and extent of the disease, and the dosage form and administration mode, but in the case of intravenous injection, it is 0.01. It can be administered in a dose of 0.1 to 10 mg OgZkg. Sulfated hyaluronic acid and other sulfated acidic mucopolysaccharides and sulfated dextran do not show acute toxicity even at a dose of 200 rag Zkg or more. May be used.
以上のような本発明の抗炎症剤は、 コブラ毒の投与により惹起される 実験動物モデルの血管透過性、 炎症に伴う出血およびミエ口パーォキシ デース （M P O ) 活性を有意に抑制することから広く、 抗炎症剤として、 特に、 A R D S、 虚血性心疾患、 虚血性脳疾患、 慢性関節リューマチ、 ア トピー性皮膚炎、 および臓器移植後の浸潤の予防または治療に利用で きる。  The anti-inflammatory agent of the present invention as described above is widely used because it significantly suppresses vascular permeability, bleeding associated with inflammation, and myeloperoxidase (MPO) activity in an experimental animal model induced by administration of cobra venom. It can be used as an anti-inflammatory agent, especially for the prevention or treatment of ARDS, ischemic heart disease, ischemic brain disease, rheumatoid arthritis, atopic dermatitis, and invasion after organ transplantation.
以下、 具体例を示して本発明をさらに詳細に説明するが、 これらによ り本発明が限定されるものではない。  Hereinafter, the present invention will be described in more detail with reference to specific examples, but the present invention is not limited thereto.
製造例 1 高分子ヒアルロン酸 （HMWHA、 分子量 1. 300 k D a ) の 20 Omgと硫酸 ' トリノチルァミ ン複合体 （Aldrich) 400 mgをジメチル ホルムアミ ド 6 mLに溶解し、 油浴中 50〜60°Cにて 1週間撹拌した。 反応液を真空ポンプにて減圧濃縮した後、 残渣を水に溶解し、 脱イオン 水に対して 1夜透析し、 次いで凍結乾燥した。 得られた乾固物を水 2m Lに溶解し、 卜リフルォロ酢酸 （HMWH Aの水酸基総数の 1.5倍モ ル相当量） を加え、 室温にて 1時間撹拌した。 反応液を透析後、 凍結乾 燥して硫酸化率約 60%の硫酸化ヒアル口ン酸を 20 Omg得た。 Production Example 1 Dissolve 20 Omg of high molecular weight hyaluronic acid (HMWHA, molecular weight 1.300 kDa) and 400 mg of 'trinotylamine sulfate complex (Aldrich) in 6 mL of dimethylformamide, and in an oil bath at 50-60 ° C. Stirred for one week. After the reaction solution was concentrated under reduced pressure using a vacuum pump, the residue was dissolved in water, dialyzed against deionized water overnight, and then freeze-dried. The obtained dried product was dissolved in 2 mL of water, and trifluoroacetic acid (equivalent to 1.5 times the total number of hydroxyl groups of HMWHA) was added, followed by stirring at room temperature for 1 hour. After dialysis, the reaction solution was freeze-dried to obtain 20 mg of sulfated hyaluronic acid having a sulfation rate of about 60%.
製造例 2 Production Example 2
高分子ヒアルロン酸に代え低分子量 （LMWHA、 分子量 40 kDa) を用いたこと以外、 製造例 1と同様の操作を繰り返した。 こう して約 5 0〜60%の硫酸化率をもつ硫酸化低分子量ヒアルロン酸を得た。  The same operation as in Production Example 1 was repeated, except that low molecular weight (LMWHA, molecular weight 40 kDa) was used instead of high molecular weight hyaluronic acid. Thus, a sulfated low molecular weight hyaluronic acid having a sulfation rate of about 50 to 60% was obtained.
抗炎症作用の評価試験 Evaluation test for anti-inflammatory action
(1) 炎症モデル動物の作製および炎症の評価法  (1) Preparation of inflammation model animal and evaluation method of inflammation
特定の病原体に感染していない成体の雄ロング-エバンス （Long-Ev ans) ラッ ト （250〜 350 g) を使用した。 コブラ毒 （C VF) はコ ブラ (Naja naja) 粗製毒から Tillら、 J. Clin. I nvest., 69, 1126〜 1135, 1982に記載の方法で単離した。 体重 1 kg当り 20 Uの C V Fを125 I - B S A (0.5 Ci) および51 C r-ラッ ト赤血 球 （RBC) の一定量の共ラッ 卜の静脈内に注入した。 Adult male Long-Evans rats (250-350 g) that were not infected with a particular pathogen were used. Cobra venom (CVF) was isolated from crude cobra (Naja naja) venom by the method described by Till et al., J. Clin. Invest., 69, 1126-1135, 1982. 20 U / kg body weight of CVF was injected intravenously into a fixed volume of 125 I-BSA (0.5 Ci) and 51 Cr-rat erythrocytes (RBC).
動物を塩酸ケタ ミ ン （ 10 OmgZkg) (Parke Davis and Co.) で麻酔し、 CVF注入後 30分目に背部大静脈から採血した。 陰性対照 動物は、 C V Fの代わりにリ ン酸緩衝溶液 （PBS， pH 7.4 ) を使用 したことを除き、 上記と同様に処置した。 30分間隔で、 肺の血管系を PBS 1 OmLを用いて右心室を介して灌流した。 次に肺を摘出し、 滅 菌生理食塩水 1 OmLで上記血管系を灌流し、 次いで組織内に残存する 放射能量をガンマシンチレーションカウンターで測定した。 なお陽性対 照は被検物質を投与しなかった場合の測定値である。 Animals were anesthetized with ketamine hydrochloride (10 OmgZkg) (Parke Davis and Co.) and blood was collected from the dorsal vena cava 30 minutes after CVF injection. Negative control animals were treated as above, except that phosphate buffered saline (PBS, pH 7.4) was used instead of CVF. At 30 minute intervals, the lung vasculature Perfused through the right ventricle with 1 OmL of PBS. Next, the lungs were removed, and the vascular system was perfused with 1 OmL of sterile physiological saline, and then the amount of radioactivity remaining in the tissues was measured with a gamma scintillation counter. The positive control is the value measured when the test substance was not administered.
肺の損傷を、 肺血管透過性の増大 （死亡時に得た静脈の血液 lniL中 に存在する放射能量に対する肺組織内に存在する125 I - B S A放射能量 の比を求めることによる） と同様に血液の放射能に対する比率として定 量した出血 （51Cr-RBCの放射能量に基づく） によって特定した。 肺 損傷の防護は下記式により算出した。 Pulmonary damage is measured by increasing pulmonary vascular permeability (by determining the ratio of the amount of 125 I-BSA radioactivity present in lung tissue to the amount of radioactivity present in the venous blood lniL obtained at death) as well as blood. Hemorrhage was determined by bleeding (based on 51 Cr-RBC radioactivity) as a percentage of radioactivity. The protection against lung injury was calculated by the following formula.
防護 （％) = 1 O Ox [被検物質値一陰性対照 （PB S) 値/陽性対照 値一陰性対照 （P B S) 値]  Protection (%) = 1 O Ox [Test substance value-Negative control (PBS) value / Positive control value-Negative control (PBS) value]
(2) 組織ミエ口パーォキシデース （ΜΡΟ) 活性  (2) Tissue mie mouth peroxidase (ΜΡΟ) Activity
好中球浸潤の指標として、 組織の MP 0活性を測定した。 グリコゲン 刺激ラッ 卜の一定数の腹腔内好中球を正常なラッ 卜の肺に加え、 組織を ホモジナイズし、 次いで抽出した後、 標準曲線を作成した （Warrenら、 J. Clin. I nvest., 84、 1873 - 1882, 1989参照） 。 肺サンプルを、 謹液 (5 OmMリ ン酸塩、 pH6.0) 6mLを用いホ モジナイザー （Polytron： Tekmar Co. , ) を 4に設定し、 4 x 10 秒ホモジナイズし、 次いで 4 °Cで遠心 （3, 000g、 30分） した。 上 澄液中の MPO活性を、 0 -ジァニシジンの存在下で H 202の消費から もたらされる吸収度 （46 Onm) の変化を測定することによって評価し た。 As an indicator of neutrophil infiltration, the MP0 activity of the tissue was measured. After a certain number of intraperitoneal neutrophils of glycogen-stimulated rats were added to the lungs of normal rats, the tissues were homogenized and extracted, and a standard curve was prepared (Warren et al., J. Clin. Invest., 84, 1873-1882, 1989). The lung sample was homogenized with a homogenizer (Polytron: Tekmar Co.,) set to 4 using 6 mL of a solution (5 OmM phosphate, pH 6.0), homogenized for 4 x 10 seconds, and then centrifuged at 4 ° C. (3,000g, 30 minutes). The MPO activity in the supernatant, 0 - H 2 0 absorbance resulting from the second consumer in the presence of Jianishijin changes in (46 onm) was assessed by measuring.
(3) 結果  (3) Result
各種の被検物質を、 上記 （1) の CVFを投与する直前にそれぞれ 1 mgZkg静脈内投与した場台の結果を下記表に示す。 試験 被検物質 肺損傷の低減率（％) Immediately before the administration of the CVF of (1) above, The results of the platform after intravenous administration of mgZkg are shown in the table below. Test Analyte Reduction rate of lung damage (%)
No 静 注 量 透過性 出血 M P 0 No Injection volume Permeability Bleeding M P 0
1. 硫酸化 HMWH A 1 mg 84 63 60 (.001. Sulfated HMWH A 1 mg 84 63 60 (.00
2. 硫酸化 LMWH A 1 mg 62 31 未測定2. Sulfated LMWH A 1 mg 62 31 Not determined
3. へパリン硫酸 * 1 mg 43 -6 未測定3. Heparin sulfate * 1 mg 43 -6 Not measured
4. 硫酸化デキストラン 1 mg 8 一 31 未測定4. Sulfated dextran 1 mg 8 1 31 Not determined
5. HMWH A (対照） 1 mg 4 0 05. HMWH A (control) 1 mg 400
6. Sialyl- Lews X (比較) *** 1 mg 35 6 未測定6. Sialyl-Lews X (comparison) *** 1 mg 35 6 Not determined
* 和光純薬社製 * Wako Pure Chemical Industries
** コーヮ社製  ** Made by Koryu
*** M. S . Mulligan ら、 Nature, Vol. 364(1993) pp. 149-150 参照  *** See M.S.Muligan et al., Nature, Vol. 364 (1993) pp. 149-150.
以上に示すように、 本発明の硫酸化多糖類はコブラ毒 （CVF) の投 与により惹起される肺損傷を有意に防護することができる。  As described above, the sulfated polysaccharide of the present invention can significantly protect lung damage caused by administration of cobra venom (CVF).
製剤例 Formulation example
組成  Composition
硫酸化 HMWH A 1 g  Sulfated HMWH A 1 g
等張化リ ン酸緩衝液 （PB S) 1 L  Isotonic phosphate buffer (PBS) 1 L
調整 Adjustment
滅菌した P B Sに硫酸化 HMWH Aを溶解させる。  Dissolve sulfated HMWH A in sterile PBS.
産業上の利用性 Industrial applicability
本発明によれば、 従来の抗炎症剤と異なる作用機序をもつ抗炎症剤が 提供される。 本発明の抗炎症剤は硫酸化酸性ムコ多糖類または硫酸化デ キス トランを有効成分として使用することにより、 強い抗炎症作用等を 示す薬剤、 ならびに炎症、 特に A R D S、 虚血性心疾患、 虚血性脳疾患、 慢性関節リュ一マチ、 ァ トピー性皮庸炎および臓器移植後の浸潤の治療 または予防方法が提供される。 According to the present invention, anti-inflammatory agents having a different mechanism of action from conventional anti-inflammatory agents Provided. The anti-inflammatory agent of the present invention uses a sulfated acidic mucopolysaccharide or a sulfated dextran as an active ingredient, thereby exhibiting a strong anti-inflammatory action and the like, and inflammation, particularly ARDS, ischemic heart disease, ischemic Methods are provided for treating or preventing brain disease, rheumatoid arthritis, atopic dermatitis and infiltration after organ transplantation.
従って本発明は製薬工業において利用性を有する。  Thus, the present invention has utility in the pharmaceutical industry.

Claims

請求の範囲 The scope of the claims
1. 硫酸化酸性ムコ多糖類、 硫酸化デキス トランおよびそれらの生理学 的に許容される塩からなる群より選ばれる多糖類の有効量と、 製薬学的 助剤とを含んでなる抗炎症剤。  1. An anti-inflammatory agent comprising an effective amount of a polysaccharide selected from the group consisting of sulfated acidic mucopolysaccharide, sulfated dextran and physiologically acceptable salts thereof, and a pharmaceutical auxiliary.
2. 硫酸化酸性ムコ多糖類、 硫酸化デキス トランおよびそれらの生理学 的に許容される塩からなる群より選ばれる多糖類を用いる炎症の治療方 法。  2. A method for treating inflammation using a polysaccharide selected from the group consisting of sulfated acidic mucopolysaccharide, sulfated dextran and physiologically acceptable salts thereof.
3. 硫酸化酸性ムコ多糖類、 硫酸化デキス トランおよびそれらの生理学 的に許容される塩からなる群より選ばれる多糖類を用いる成人性呼吸切 迫症候群 （ARD S) 、 虚血性心疾患、 虚血性脳疾患、 慢性関節リュー マチ、 ァ トピー性皮膚炎および臓器移植後の浸潤からなる群より選ばれ る疾患の治療方法。  3. Adult respiratory distress syndrome (ARDS), ischemic heart disease, ischemia using polysaccharides selected from the group consisting of sulfated acidic mucopolysaccharides, sulfated dextrans and their physiologically acceptable salts A method for treating a disease selected from the group consisting of blood brain disease, rheumatoid arthritis, atopic dermatitis, and infiltration after organ transplantation.
4. 多糖類が硫酸化ヒアル口ン酸である請求の範囲第 3項記載の治療方 o  4. The method according to claim 3, wherein the polysaccharide is sulfated hyaluronic acid.
5. 多糖類が硫酸化ヒアルロン酸であり、 そして疾患が ARD Sである 請求の範囲第 3項記載の治療方法。  5. The method according to claim 3, wherein the polysaccharide is sulfated hyaluronic acid, and the disease is ARDS.
6. 炎症の治療用薬剤を製造するための硫酸化酸性ムコ多糖類、 硫酸化 デキス トランおよびそれらの生理学的に許容される塩からなる群より選 ばれる多糖類の使用。  6. Use of a polysaccharide selected from the group consisting of sulfated acidic mucopolysaccharides, sulfated dextrans and their physiologically acceptable salts for the manufacture of a medicament for the treatment of inflammation.
7. 成人性呼吸切迫症候群 （ARD S) 、 虚血性心疾患、 虚血性脳疾患、 慢性関節リユ ーマチ、 アトピー性皮庸炎および臓器移植後の浸潤からな る群より選ばれる疾患の治療用薬剤を製造するための硫酸化酸性ムコ多 糖類、 硫酸化デキストランおよびそれらの生理学的に許容される塩から なる群より選ばれる多糖類の使用。 7. Medication for the treatment of adult respiratory distress syndrome (ARDS), ischemic heart disease, ischemic brain disease, rheumatoid arthritis, atopic dermatitis and invasion after organ transplantation Use of a polysaccharide selected from the group consisting of a sulfated acidic mucopolysaccharide, a sulfated dextran and a physiologically acceptable salt thereof for the production of a saccharide.
8. 多糖類が硫酸化ヒアルロン酸である請求の範囲第 6または 7項記載 の使用。 8. Use according to claim 6 or 7, wherein the polysaccharide is sulfated hyaluronic acid.
9. 疾患が ARD Sである請求の範囲第 6〜8項のいずれかに記載の使 用 ο  9. Use according to any one of claims 6 to 8, wherein the disease is ARDS ο
PCT/JP1996/000239 1995-02-07 1996-02-06 Antiinflammatory agents WO1996024362A1 (en)

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US5872109A (en) 1999-02-16
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